BIODISTRIBUTION OF LIPOSOMES CONTAINING SYNTHETIC GALACTOSE-TERMINATED DIACYLGLYCERYL-POLY(ETHYLENEGLYCOL)S

We describe the synthesis of biodegradable poly(ethyleneglycol)-couple d galactolipids in which the galactose moiety is separated from a diac ylglyceride lipid anchor by poly(ethylene glycol) chains of 10, 20 or 40 oxyethylene residues (PEG(10/20/40)). These Gal-PEG lipids (Gal-PEG -Lip) were incorporated in the bilayer of liposomes. The surface expos ure of the galactose was investigated by aggregation experiments with ricinus communis agglutinin 120. Only the liposomes containing the PEG (10) galactolipid aggregated with the lectin. Therefore Liposomes were prepared containing Gal-PEG(10)-Lip and a trace amount of [H-3]choles teryl oleyl ether with an average diameter of approximately 100 nn and injected intravenously into rats. The Gal-PEG(10)-Lip liposomes were cleared from plasma with a T1/2 of 0.3 h. Identically sized and compos ed control liposomes without the Gal-PEG(10)-Lip had a T1/2 of approxi mately 12 h. The rapid plasma elimination of the Gal-PEG(10)-Lip lipos omes could be attributed entirely to increased uptake by the liver amo unting to more than 90% of injected dose, Uptake by the spleen was dec reased to less than 1% of injected dose. A single injection of N-acety lgalactosamine 1 min prior to Gal-PEG-Lip liposome administration redu ced the initial rate of plasma clearance to control levels. The increa sed liver uptake was almost entirely attributable to increased uptake by the Kupffer cells. Incorporation of PEG-DSPE in the Gal-PEG(10)-Lip liposomes only partially reversed the effect of the galactolipid with respect to liver and spleen uptake as well as intrahepatic distributi on. These experiments demonstrate that liposome surface-exposed galact ose residues, even if attached at the distal end of a poly(ethylenegly col) chain anchored in the liposomal bilayer are effectively recognize d by the galactose particle receptor on the Kupffer cells but fail to achieve significant targeting to the asialoglycoprotein receptor on th e hepatocytes.